阻断 STAT3 可通过巨噬细胞驱动的炎症改善 LPS 引起的肾损伤。

IF 8.2 2区 生物学 Q1 CELL BIOLOGY
Song-Hee Lee, Kyu Hong Kim, Seong Min Lee, Seong Joon Park, Sunhwa Lee, Ran-Hui Cha, Jae Wook Lee, Dong Ki Kim, Yon Su Kim, Sang-Kyu Ye, Seung Hee Yang
{"title":"阻断 STAT3 可通过巨噬细胞驱动的炎症改善 LPS 引起的肾损伤。","authors":"Song-Hee Lee, Kyu Hong Kim, Seong Min Lee, Seong Joon Park, Sunhwa Lee, Ran-Hui Cha, Jae Wook Lee, Dong Ki Kim, Yon Su Kim, Sang-Kyu Ye, Seung Hee Yang","doi":"10.1186/s12964-024-01841-1","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Signal transducer and activator of transcription 3 (STAT3), a multifaceted transcription factor, modulates host immune responses by activating cellular response to signaling ligands. STAT3 has a pivotal role in the pathophysiology of kidney injury by counterbalancing resident macrophage phenotypes under inflammation conditions. However, STAT3's role in acute kidney injury (AKI), particularly in macrophage migration, and in chronic kidney disease (CKD) through fibrosis development, remains unclear.</p><p><strong>Methods: </strong>Stattic (a JAK2/STAT3 inhibitor, 5 mg/kg or 10 mg/kg) was administered to evaluate the therapeutic effect on LPS-induced AKI (L-AKI) and LPS-induced CKD (L-CKD), with animals sacrificed 6-24 h and 14 days post-LPS induction, respectively. The immune mechanisms of STAT3 blockade were determined by comparing the macrophage phenotypes and correlated with renal function parameters. Also, the transcriptomic analysis was used to confirm the anti-inflammatory effect of L-AKI, and the anti-fibrotic role was further evaluated in the L-CKD model.</p><p><strong>Results: </strong>In the L-AKI model, sequential increases in BUN and blood creatinine levels were time-dependent, with a marked elevation of 0-6 h after LPS injection. Notably, two newly identified macrophage subpopulations (CD11b<sup>high</sup>F4/80<sup>low</sup> and CD11b<sup>low</sup>F4/80<sup>high</sup>), exhibited population changes, with an increase in the CD11b<sup>high</sup>F4/80<sup>low</sup> population and a decrease in the CD11b<sup>low</sup>F4/80<sup>high</sup> macrophages. Corresponding to the FACS results, the tubular injury score, NGAL, F4/80, and p-STAT3 expression in the tubular regions were elevated. STAT3 inhibitor injection in L-AKI and L-CKD mice reduced renal injury and fibrosis. M2-type subpopulation with CD206 in CD11b<sup>low</sup>F4/80<sup>high</sup> population increased in the Stattic-treated group compared with that in the LPS-alone group in the L-AKI model. Additionally, STAT3 inhibitor reduced inflammation driven by LPS-stimulated macrophages and epithelial cells injury in the co-culture system. Transcriptomic profiling identified 3 common genes in the JAK-STAT, TLR, and TNF signaling pathways and 11 common genes in the LPS with macrophage response. The PI3K-AKT (IL-6, Akt3, and Pik3r1) and JAK-STAT pathways were determined as potential Stattic targets. Further confirmation through mRNA and protein expressions analyses showed that Stattic treatment reduced inflammation in the L-AKI and fibrosis in the L-CKD mice.</p><p><strong>Conclusions: </strong>STAT3 blockade effectively mitigated inflammation by retrieving the CD11b<sup>low</sup>F4/80<sup>high</sup> population, further emphasizing the role of STAT3-associated macrophage-driven inflammation in kidney injury.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.2000,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11453053/pdf/","citationCount":"0","resultStr":"{\"title\":\"STAT3 blockade ameliorates LPS-induced kidney injury through macrophage-driven inflammation.\",\"authors\":\"Song-Hee Lee, Kyu Hong Kim, Seong Min Lee, Seong Joon Park, Sunhwa Lee, Ran-Hui Cha, Jae Wook Lee, Dong Ki Kim, Yon Su Kim, Sang-Kyu Ye, Seung Hee Yang\",\"doi\":\"10.1186/s12964-024-01841-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Signal transducer and activator of transcription 3 (STAT3), a multifaceted transcription factor, modulates host immune responses by activating cellular response to signaling ligands. STAT3 has a pivotal role in the pathophysiology of kidney injury by counterbalancing resident macrophage phenotypes under inflammation conditions. However, STAT3's role in acute kidney injury (AKI), particularly in macrophage migration, and in chronic kidney disease (CKD) through fibrosis development, remains unclear.</p><p><strong>Methods: </strong>Stattic (a JAK2/STAT3 inhibitor, 5 mg/kg or 10 mg/kg) was administered to evaluate the therapeutic effect on LPS-induced AKI (L-AKI) and LPS-induced CKD (L-CKD), with animals sacrificed 6-24 h and 14 days post-LPS induction, respectively. The immune mechanisms of STAT3 blockade were determined by comparing the macrophage phenotypes and correlated with renal function parameters. Also, the transcriptomic analysis was used to confirm the anti-inflammatory effect of L-AKI, and the anti-fibrotic role was further evaluated in the L-CKD model.</p><p><strong>Results: </strong>In the L-AKI model, sequential increases in BUN and blood creatinine levels were time-dependent, with a marked elevation of 0-6 h after LPS injection. Notably, two newly identified macrophage subpopulations (CD11b<sup>high</sup>F4/80<sup>low</sup> and CD11b<sup>low</sup>F4/80<sup>high</sup>), exhibited population changes, with an increase in the CD11b<sup>high</sup>F4/80<sup>low</sup> population and a decrease in the CD11b<sup>low</sup>F4/80<sup>high</sup> macrophages. Corresponding to the FACS results, the tubular injury score, NGAL, F4/80, and p-STAT3 expression in the tubular regions were elevated. STAT3 inhibitor injection in L-AKI and L-CKD mice reduced renal injury and fibrosis. M2-type subpopulation with CD206 in CD11b<sup>low</sup>F4/80<sup>high</sup> population increased in the Stattic-treated group compared with that in the LPS-alone group in the L-AKI model. Additionally, STAT3 inhibitor reduced inflammation driven by LPS-stimulated macrophages and epithelial cells injury in the co-culture system. Transcriptomic profiling identified 3 common genes in the JAK-STAT, TLR, and TNF signaling pathways and 11 common genes in the LPS with macrophage response. The PI3K-AKT (IL-6, Akt3, and Pik3r1) and JAK-STAT pathways were determined as potential Stattic targets. Further confirmation through mRNA and protein expressions analyses showed that Stattic treatment reduced inflammation in the L-AKI and fibrosis in the L-CKD mice.</p><p><strong>Conclusions: </strong>STAT3 blockade effectively mitigated inflammation by retrieving the CD11b<sup>low</sup>F4/80<sup>high</sup> population, further emphasizing the role of STAT3-associated macrophage-driven inflammation in kidney injury.</p>\",\"PeriodicalId\":55268,\"journal\":{\"name\":\"Cell Communication and Signaling\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2024-10-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11453053/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Communication and Signaling\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1186/s12964-024-01841-1\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Communication and Signaling","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s12964-024-01841-1","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

背景:信号转导和激活转录因子 3(STAT3)是一种多方面的转录因子,它通过激活细胞对信号配体的反应来调节宿主的免疫反应。STAT3 在炎症条件下通过平衡常驻巨噬细胞表型,在肾损伤的病理生理学中发挥着关键作用。然而,STAT3 在急性肾损伤(AKI)中的作用,特别是在巨噬细胞迁移中的作用,以及在慢性肾脏病(CKD)中通过纤维化发展所起的作用仍不清楚:方法:分别在LPS诱导后6-24 h和14 d处死动物,给予Stattic(一种JAK2/STAT3抑制剂,5 mg/kg或10 mg/kg)以评估其对LPS诱导的AKI(L-AKI)和LPS诱导的CKD(L-CKD)的治疗效果。通过比较巨噬细胞表型确定了 STAT3 阻断的免疫机制,并将其与肾功能参数相关联。此外,还利用转录组分析证实了 L-AKI 的抗炎作用,并进一步评估了 L-CKD 模型的抗纤维化作用:结果:在L-AKI模型中,BUN和血肌酐水平的连续升高具有时间依赖性,在注射LPS后的0-6小时内升高明显。值得注意的是,两个新发现的巨噬细胞亚群(CD11bhighF4/80-low 和 CD11blowF4/80-high)出现了群体变化,CD11bhighF4/80-low 群体增加,CD11blowF4/80-high 巨噬细胞减少。与 FACS 结果相对应的是,肾小管损伤评分、NGAL、F4/80 和肾小管区域 p-STAT3 表达的升高。给 L-AKI 和 L-CKD 小鼠注射 STAT3 抑制剂可减少肾损伤和纤维化。在 L-AKI 模型中,与单独注射 LPS 组相比,Stattic 处理组 CD11blowF4/80 高 CD206 的 M2- 型亚群增加。此外,STAT3 抑制剂还能减轻共培养系统中由 LPS 刺激的巨噬细胞和上皮细胞损伤引起的炎症。转录组分析确定了 JAK-STAT、TLR 和 TNF 信号通路中的 3 个常见基因,以及 LPS 与巨噬细胞反应中的 11 个常见基因。PI3K-AKT(IL-6、Akt3 和 Pik3r1)和 JAK-STAT 通路被确定为潜在的 Stattic 靶点。通过mRNA和蛋白质表达分析进一步证实,Stattic治疗可减轻L-AKI小鼠的炎症和L-CKD小鼠的纤维化:结论:阻断 STAT3 能通过回收 CD11blowF4/80 高人群有效缓解炎症,进一步强调了 STAT3 相关巨噬细胞驱动的炎症在肾损伤中的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
STAT3 blockade ameliorates LPS-induced kidney injury through macrophage-driven inflammation.

Background: Signal transducer and activator of transcription 3 (STAT3), a multifaceted transcription factor, modulates host immune responses by activating cellular response to signaling ligands. STAT3 has a pivotal role in the pathophysiology of kidney injury by counterbalancing resident macrophage phenotypes under inflammation conditions. However, STAT3's role in acute kidney injury (AKI), particularly in macrophage migration, and in chronic kidney disease (CKD) through fibrosis development, remains unclear.

Methods: Stattic (a JAK2/STAT3 inhibitor, 5 mg/kg or 10 mg/kg) was administered to evaluate the therapeutic effect on LPS-induced AKI (L-AKI) and LPS-induced CKD (L-CKD), with animals sacrificed 6-24 h and 14 days post-LPS induction, respectively. The immune mechanisms of STAT3 blockade were determined by comparing the macrophage phenotypes and correlated with renal function parameters. Also, the transcriptomic analysis was used to confirm the anti-inflammatory effect of L-AKI, and the anti-fibrotic role was further evaluated in the L-CKD model.

Results: In the L-AKI model, sequential increases in BUN and blood creatinine levels were time-dependent, with a marked elevation of 0-6 h after LPS injection. Notably, two newly identified macrophage subpopulations (CD11bhighF4/80low and CD11blowF4/80high), exhibited population changes, with an increase in the CD11bhighF4/80low population and a decrease in the CD11blowF4/80high macrophages. Corresponding to the FACS results, the tubular injury score, NGAL, F4/80, and p-STAT3 expression in the tubular regions were elevated. STAT3 inhibitor injection in L-AKI and L-CKD mice reduced renal injury and fibrosis. M2-type subpopulation with CD206 in CD11blowF4/80high population increased in the Stattic-treated group compared with that in the LPS-alone group in the L-AKI model. Additionally, STAT3 inhibitor reduced inflammation driven by LPS-stimulated macrophages and epithelial cells injury in the co-culture system. Transcriptomic profiling identified 3 common genes in the JAK-STAT, TLR, and TNF signaling pathways and 11 common genes in the LPS with macrophage response. The PI3K-AKT (IL-6, Akt3, and Pik3r1) and JAK-STAT pathways were determined as potential Stattic targets. Further confirmation through mRNA and protein expressions analyses showed that Stattic treatment reduced inflammation in the L-AKI and fibrosis in the L-CKD mice.

Conclusions: STAT3 blockade effectively mitigated inflammation by retrieving the CD11blowF4/80high population, further emphasizing the role of STAT3-associated macrophage-driven inflammation in kidney injury.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
11.00
自引率
0.00%
发文量
180
期刊介绍: Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信